This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The association between CD4+ T-cell depletion and an accelerated rate of disease progression is well established for HIV infection in humans and simian immunodeficiency virus (SIV) infection in macaques. Prior to our studies, SIV infection in its natural primate host (i.e. sooty mangabeys) was observed to result in near normal levels of CD4+ T-cells despite similar plasma viral loads. Following transfer of plasma from an SIV+ mangabey in 2000 and 2006, five mangabeys exhibited a decline in CD4+ T cell levels to below 100 cells/ul of blood, also observed in lymph nodes. These levels have remained between 18 and 100 cells/ul of blood for the past decade. Through microneutralization assays and hemaglutination inhibition it was determined that all five mangabeys were able to mount effective antibody responses to the influenza vaccination, even with the very low levels of CD4+ T cells. Low immune activation and preserved immune responses observed in these mangabeys were associated with the presence of CD3+CD4-CD8- double-negative T cells with a central memory phenotype that are capable of producing Th1, Th2, and Th17 cytokines. These studies indicate that CD4+ T cell depletion in SIV-infected natural hosts need not result in immune dysfunction. Indeed, SIV-infected mangabeys do not appear to rely entirely on CD4+ T cells to maintain immunity and identify double-negative T cells in this species as a potential subset capable of performing CD4-like helper functions. Further characterization of these double-negative T cells is underway.